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1.  Matrix metalloproteases and their inhibitors are altered in torn rotator cuff tendons, but also in the macroscopically and histologically intact portion of those tendons 
We evaluated whether matrix metalloproteases and their inhibitors are involved in extracellular matrix remodelling and degradation of chronic rotator cuff tears. Tendon samples were harvested from 13 patients who underwent arthroscopic repair of a rotator cuff tear. Supraspinatus specimens were harvested en bloc from the arthroscopically intact middle portion of the tendon, more than 1 cm lateral to the torn edge, from the lateral edge of the tear, and from the superior margin of the macroscopically intact subscapularis tendon, used as control. The collagenases, the stromelysins, and the tissue inhibitors of metalloprotease arrays were analyzed blindly by multiplex sandwich ELISA in each specimen. Histological evidence of tendinopathy was present in all patients with a rotator cuff tear, but not in the macroscopically intact subscapularis tendon. There were significantly increased levels of MMP 1, MMP 2, MMP 3, TIMP-1, and TIMP-2 in all specimens examined, including the macroscopically intact portion of the supraspinatus tendon and the subscapularis (control specimens). The levels of specific matrix metalloproteases and their inhibitors are altered in torn rotator cuff tendons, but also in the macroscopically and histologically intact tendons. These changes extended medially to the site of tendon tear, and to other tendons.
PMCID: PMC3838321  PMID: 24367772
gene expression; rotator cuff; surgery; outcome
2.  Expression of matrix metalloproteinases 1, 3, and 9 in degenerated long head biceps tendon in the presence of rotator cuff tears: an immunohistological study 
Long head biceps (LHB) degeneration, in combination with rotator cuff tears, can be a source of chronic shoulder pain. LHB tenotomy reduces pain and improves joint function although the pathophysiological context is not well understood. Tendon integrity depends on the extracellular matrix (ECM), which is regulated by matrix metalloproteinases (MMP). It is unclear which of these enzymes contribute to LHB but we chose to study MMP 1, 3, and 9 and hypothesized that one or more of them may be altered in LHB, whether diagnosed preoperatively or intraoperatively. We compared expression of these MMPs in both LHB and healthy tendon samples.
LHB samples of 116 patients with degenerative rotator cuff tears were harvested during arthroscopic tenotomy. Patients were assigned to 4 groups (partial thickness tear, full thickness tear, cuff arthropathy, or control) based upon intraoperative findings. Partial and full thickness tears were graded according to Ellman and Bateman's classifications, respectively. MMP expression was determined by immunohistochemistry.
MMP 1 and 9 expression was significantly higher in the presence of rotator cuff tears than in controls whereas MMP 3 expression was significantly decreased. MMP 1 and 9 expression was significantly higher in articular-sided than bursal-sided partial thickness tears. No significant association was found between MMP 1 and 9 expression and full thickness tears, and the extent of the cuff tear by Bateman's classification.
Increased MMP 1 and 9 expression, and decreased MMP 3 expression are found in LHB degeneration. There is a significant association between the size and location of a rotator cuff tear and MMP expression.
PMCID: PMC2998463  PMID: 21108787
3.  Correlation of Plasma MMP-1 and TIMP-1 Levels and the Colonic Mucosa Expressions in Patients with Ulcerative Colitis 
Mediators of Inflammation  2009;2009:275072.
Background. Both plasma and mucosal levels of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) have been shown to be independently correlated with ulcerative colitis (UC), but their relationship with each other and to disease severity remains unclear. This study aims to evaluate the relationship between colonic mucosal and plasma levels of MMP-1 and TIMP-1 with each other and with the severity of ulcerative colitis (UC). Methods. Colonic mucosal lesions and venous blood samples were collected from 30 patients with UC and 15 normal subjects. Real-time reverse transcription-PCR and immunohistochemistry were used to determine colonic mucosal MMP-1 and TIMP-1 expression; ELISA was used to measure plasma levels of MMP-1 and TIMP-1. Results. Expression of colonic mucosal and plasma MMP-1 and TIMP-1 in patients with UC was significantly higher than that of controls (P < .05), and was positively correlated with disease severity (P < .05). Plasma MMP-1 and TIMP-1 levels were well correlated with their corresponding expression in colonic mucosa (P < .05, r = 0.805 and 0.908). Conclusion. Plasma MMP-1 and TIMP-1 levels reflect their colonic mucosal expression to some extent in patients with UC. Plasma MMP-1 and TIMP-1, in particular, demonstrate the potential to become biomarkers to clinically diagnose UC, predict its severity, and guide further therapy.
PMCID: PMC2774532  PMID: 19911067
4.  Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris 
PLoS ONE  2011;6(4):e19340.
There is a growing interest for matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in plasma as novel biomarkers in coronary artery disease (CAD). We aimed to identify the sources of MMP-8, MMP-9, TIMP-1 and TIMP-2 among peripheral blood cells and further explore whether gene expression or protein release was altered in patients with stable angina pectoris (SA).
In total, plasma MMP-9 was measured in 44 SA patients and 47 healthy controls. From 10 patients and 10 controls, peripheral blood mononuclear cells (PBMC) and neutrophils were isolated and stimulated ex vivo. MMPs, TIMPs and myeloperoxidase were measured in plasma and supernatants by ELISA. The corresponding gene expression was measured by real-time PCR.
Neutrophils were the dominant source of MMP-8 and MMP-9. Upon moderate stimulation with IL-8, the neutrophil release of MMP-9 was higher in the SA patients compared with controls (p<0.05). In PBMC, the TIMP-1 and MMP-9 mRNA expression was higher in SA patients compared with controls, p<0.01 and 0.05, respectively. There were no differences in plasma levels between patients and controls except for TIMP-2, which was lower in patients, p<0.01.
Measurements of MMPs and TIMPs in plasma may be of limited use. Despite similar plasma levels in SA patients and controls, the leukocyte-derived MMP-9 and TIMP-1 are significantly altered in patients. The findings indicate that the leukocytes are more prone to release and produce MMP-9 in symptomatic and angiographically verified CAD—a phenomenon that may have clinical implications in the course of disease.
PMCID: PMC3084822  PMID: 21559401
5.  Differential Expression of Matrix Metalloproteinases in the Serum of Patients with Mucopolysaccharidoses 
JIMD Reports  2011;3:59-66.
Mucopolysaccharidoses (MPS) represent a heterogeneous group of hereditary disorders, characterized by accumulation of glycosaminoglycans within the lysosomes. The objective of this study was to elucidate the expression and activity of matrix metalloproteinases (MMPs) in the serum of pediatric patients with MPS. Serum gelatinase activity was assessed by gelatin zymography and the concentration of circulating MMP-2, MMP-9, and of tissue inhibitors of MMPs (TIMP)-1 and TIMP-2 was measured by ELISA in the serum of seven patients with MPS (five with MPS III, 1 with MPS II and 1 with MPS VI), and healthy age- and sex-matched participants. Serum activity and protein levels of MMP-9 were significantly reduced whereas of MMP-2 were significantly increased in patients with MPS III, as compared to controls. There were no significant alterations in serum protein levels of TIMP-1 and TIMP-2 in patients with MPS III, as compared to controls. In MPS II, proMMP-2 activity and protein levels of MMP-2 were significantly increased, as compared to control. In MPS VI, enzyme replacement therapy reduced the activity and protein levels of MMP-9 up to 4 months after the initiation of treatment. The reported alterations in the expression of MMPs in the serum of patients with MPS suggest that these molecules may be used as potential biomarkers for the diagnosis, follow-up and response to therapy in patients with MPS.
PMCID: PMC3509861  PMID: 23430874
6.  Matrix Metalloproteinases and Their Inhibitors: Correlation with Invasion and Metastasis in Oral Cancer 
Matrix metalloproteinases (MMPs) have been implicated in invasion and metastasis of various malignancies. The study evaluated a comprehensive profile of MMP-2 and MMP-9 and their inhibitors, tissue inhibitor of metalloproteinases-2 (TIMP-2) and tissue inhibitor of metalloproteinases-1 (TIMP-1), respectively in 50 controls and 75 patients with oral squamous cell carcinoma (OSCC). Blood samples from controls and patients as well as malignant and adjacent normal tissues from the patients were collected. The study examined pro, active and total forms of MMP-2 and MMP-9 using zymography. Enzyme-linked immunoassay (ELISA) and reverse transcription polymerase chain reaction were carried out to evaluate protein levels and mRNA expression; respectively, for the MMPs and TIMPs. Plasma pro, active and total MMP-2, MMP-9 as well as TIMP-1 and TIMP-2 levels were significantly higher in oral cancer patients as compared to the controls. mRNA expression of the MMPs and TIMPs was significantly higher in malignant tissues as compared to adjacent normal tissues. A significant positive correlation was observed between levels of proMMP-9 and active MMP-9 with differentiation, stage and infiltration. ProMMP-2 and active MMP-2 exhibited significant positive correlation with differentiation and lymph node involvement. The multivariate analysis of ELISA results revealed a significant positive correlation between MMP-2, TIMP-1 and TIMP-2 levels with lymph node involvement, stage and differentiation. The receiver operating characteristic curve (ROC) analysis showed that the levels of MMPs and TIMPs have significant discriminatory efficacy to differentiate between controls and patients. The results indicate that MMP-2, MMP-9, TIMP-1 and TIMP-2 have significant clinical usefulness for oral cancer patients. Zymographic analysis is a simple, cost effective, rapid and sensitive alternative assay.
PMCID: PMC3001841  PMID: 21731196
MMPs; TIMPs; Oral cancer; Zymography; Metastasis; Invasion
7.  Rotator cuff tear reduces muscle fiber specific force production and induces macrophage accumulation and autophagy 
Full-thickness tears to the rotator cuff can cause severe pain and disability. Untreated tears progress in size and are associated with muscle atrophy and an infiltration of fat to the area, a condition known as “fatty degeneration.” To improve the treatment of rotator cuff tears, a greater understanding of the changes in the contractile properties of muscle fibers and the molecular regulation of fatty degeneration is essential. Using a rat model of rotator cuff injury, we measured the force generating capacity of individual muscle fibers and determined changes in muscle fiber type distribution that develop after a full thickness rotator cuff tear. We also measured the expression of mRNA and miRNA transcripts involved in muscle atrophy, lipid accumulation, and matrix synthesis. We hypothesized that a decrease in specific force of rotator cuff muscle fibers, an accumulation of type IIb fibers, an upregulation in fibrogenic, adipogenic, and inflammatory gene expression occur in torn rotator cuff muscles. Thirty days following rotator cuff tear, we observed a reduction in muscle fiber force production, an induction of fibrogenic, adipogenic and autophagocytic mRNA and miRNA molecules, and a dramatic accumulation of macrophages in areas of fat accumulation.
PMCID: PMC3449033  PMID: 22696414
Rotator cuff; muscle fiber contractility; fatty degeneration; autophagy
8.  Can a high acromion index predict rotator cuff tears? 
International Orthopaedics  2012;36(5):1019-1024.
The purpose of this study was to identify the relationship between an acromion index (AI) and the size of a rotator cuff tear. The hypothesis of our study was that an AI will be higher in patients with a full-thickness tear than in patients with a partial-thickness articular-side tear, and that it can be used as a predictor for the size of a rotator cuff tear.
We included 284 patients who had been diagnosed with rotator cuff tears and had undergone arthroscopic rotator cuff repair at our institute. All patients were divided into five distinct groups (partial-thickness articular side tear, and four subgroups of full-thickness tears) depending on the size of the rotator cuff tear on arthroscopy. In each patient, an AI was measured on the pre-operative oblique coronal MR images and then analysed to determine the difference between groups.
There were statistically significant differences between the partial-thickness articular side rotator cuff tear and large-to-massive rotator cuff tear groups (p < 0.01), and the mean value of an AI was highest in the large-sized full-thickness tear group. The AI of the partial-thickness articular-side rotator cuff tear group was statistically different from the large-to-massive rotator cuff tear groups.
The AI can be a predictor which can differentiate a partial-thickness articular-side tear and a large-to-massive rotator cuff tear pre-operatively. However the AI could not provide useful guidance on predicting the differences in tear size in full-thickness tear patients. We suggest that a high AI can be one of the associated factors for progression to large-to-massive rotator cuff tears in a rotator cuff disease.
PMCID: PMC3337092  PMID: 22310972
Medicine & Public Health; Orthopedics
9.  The association between retraction of the torn rotator cuff and increasing expression of hypoxia inducible factor 1α and vascular endothelial growth factor expression: an immunohistological study 
Differing levels of tendon retraction are found in full-thickness rotator cuff tears. The pathophysiology of tendon degeneration and retraction is unclear. Neoangiogenesis in tendon parenchyma indicates degeneration. Hypoxia inducible factor 1α (HIF) and vascular endothelial growth factor (VEGF) are important inducers of neoangiogenesis. Rotator cuff tendons rupture leads to fatty muscle infiltration (FI) and muscle atrophy (MA). The aim of this study is to clarify the relationship between HIF and VEGF expression, neoangiogenesis, FI, and MA in tendon retraction found in full-thickness rotator cuff tears.
Rotator cuff tendon samples of 33 patients with full-thickness medium-sized rotator cuff tears were harvested during reconstructive surgery. The samples were dehydrated and paraffin embedded. For immunohistological determination of VEGF and HIF expression, sample slices were strained with VEGF and HIF antibody dilution. Vessel density and vessel size were determined after Masson-Goldner staining of sample slices. The extent of tendon retraction was determined intraoperatively according to Patte's classification. Patients were assigned to 4 categories based upon Patte tendon retraction grade, including one control group. FI and MA were measured on standardized preoperative shoulder MRI.
HIF and VEGF expression, FI, and MA were significantly higher in torn cuff samples compared with healthy tissue (p < 0.05). HIF and VEGF expression, and vessel density significantly increased with extent of tendon retraction (p < 0.05). A correlation between HIF/VEGF expression and FI and MA could be found (p < 0.05). There was no significant correlation between HIF/VEGF expression and neovascularity (p > 0.05)
Tendon retraction in full-thickness medium-sized rotator cuff tears is characterized by neovascularity, increased VEGF/HIF expression, FI, and MA. VEGF expression and neovascularity may be effective monitoring tools to assess tendon degeneration.
PMCID: PMC2958987  PMID: 20932296
10.  Relationships between plasma levels of matrix metalloproteinases and neurohormonal profile in patients with heart failure✩ 
European journal of heart failure  2008;10(2):125-128.
Both neurohormonal derangements and alterations in the myocardial extracellular matrix are thought to contribute to adverse ventricular remodelling that results in worsening heart failure (HF). There is also emerging preclinical information to suggest that these signalling pathways mutually regulate in HF.
To assess the relationships between plasma levels of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinase (TIMP), and neurohormonal profiles in chronic HF.
Methods and results
In this substudy of 184 HF patients enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, plasma norepinephrine and epinephrine were measured with HPLC; atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), angiotensin II, aldosterone, and endothelin-1 were measured with immunoassays; MMP-2, MMP-9, and TIMP-1 were measured with 2-site sandwich ELISA assays. We used Spearman's rank correlation to examine the relationships between plasma MMP and neurohormone levels. Circulating ANP, BNP, and endothelin-1 levels were positively correlated with MMP-2 and TIMP-1 levels. Plasma level of aldosterone showed a weak positive correlation with MMP-9, but there was no significant correlation between angiotensin II, epinephrine or norepinephrine and MMP-2, MMP-9, or TIMP-1.
These findings suggest that specific neurohormones and extracellular matrix modulators may play a coordinated role in the pathogenesis of HF.
PMCID: PMC2693229  PMID: 18234554
Heart failure; Matrix metalloproteinase; Neurohormones
11.  Full-thickness supraspinatus tears are associated with more synovial inflammation and tissue degeneration than partial-thickness tears 
The objective of this study was to determine whether the tear size of a supraspinatus tendon correlated with synovial inflammation and tendon degeneration in patients that underwent shoulder arthroscopy for rotator cuff repair. We hypothesized that increased synovial inflammation would correlate with greater tear size of the supraspinatus tendon at the time of surgery.
Materials and Methods
Tissue from the synovium, bursa, torn supraspinatus tendon and subscapularis tendon were obtained from patients during shoulder arthroscopy in order to evaluate the mRNA expression of pro-inflammatory cytokines, tissue remodeling and angiogenesis factors in the tendon, bursa, and synovium. Additional tissue was fixed to determine histological changes including inflammation, vascular ingrowths, and collagen organization.
Increased expression of IL-1β, IL-6, COX-2, MMP-9, and VEGF was found in the synovium of patients with full-thickness tears versus partial-thickness tears (p<0.05). In the supraspinatus tendon, increased expression of MMP-1, -9, and -13 and VEGF was found in the full-thickness group. The upregulation of these genes in the full-thickness group was consistent with enhanced synovium inflammation, greater vascular ingrowth and the loss of collagen organization in both supraspinatus and subscapularis tendons as determined by histology.
Increased synovium inflammation and tissue degeneration correlates with the tear size of the supraspinatus tendon. A better understanding of the relationship between synovial inflammation and the progression of tendon degeneration can help design novel and effective treatments to limit the advance of rotator cuff diseases and to improve their clinical outcomes.
Level of evidence
Basic Science, Molecular and Cell Biology Study
PMCID: PMC3156316  PMID: 21612944
Rotator cuff tear; synovial inflammation; pro-inflammatory cytokines; matrix metalloproteinase
12.  Hematopoiesis in mice is extremely resilient to wide variation in TIMP/MMP balance 
Blood cells, molecules & diseases  2008;41(2):179-187.
Tissue inhibitor of matrix metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs) and are associated with normal and pathologic extracellular matrix turnover. Because the microenvironment is critical for normal hematopoietic stem/progenitor cell function, we aimed to determine whether alterations in the TIMP/MMP balance impact upon normal hematopoiesis in mice. We have used both overexpression and knockout mouse models to determine whether early hematopoiesis is susceptible to potentially pathologic changes in TIMP/MMP level. These studies used TIMP-1−/− mice and retroviral vectors co-expressing human TIMP-1 or TIMP-2 linked with the green fluorescent protein (GFP) transduced into bone marrow (BM) cells and transplanted into lethally irradiated recipient mice. Loss of TIMP-1 in knockout mice or retroviral overexpression of TIMP-1 or TIMP-2 did not alter hematopoietic stem/progenitor function during steady-state hematopoiesis. Surprisingly, even when applying hematopoietic stress through mobilization, chemotaxis, or myelosuppression, murine hematopoiesis was not adversely affected by TIMP-1 or TIMP-2 level. We conclude that TIMP/MMP balance alone does not exert significant influence on blood cell development and homeostasis. An important corollary of these studies is that specific modulation using MMP inhibitors for cancer or immunologic therapy is unlikely to have adverse hematopoietic side effects.
PMCID: PMC2600540  PMID: 18487063
13.  Expression of tissue levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in renal cell carcinoma 
Matrix metalloproteinases (MMPs) are one of the major classes of proteolytic enzymes involved in tumor invasion and metastasis and are inhibited by naturally occurring tissue inhibitors of metalloproteinases (TIMPs). {AU Query: Please verify that corrections made to previous sentence did not alter intended meaning}. In this study, we examined the expression of MMP-2, MMP-9, membrane-type 1 (MT1)-MMP, TIMP-1, and TIMP-2 in renal tissue samples of renal cell cancer and examined the correlation between their expression and clinicopathological parameters.
Renal tissue samples from 76 patients with renal cell carcinoma were available for this study. To determine the expression of MMP-2, MMP-9, MT1-MMP, TIMP-1, and TIMP-2, semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out on tumor and normal tissues.
Mean MMP-2, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 mRNA expression in the renal cell carcinomas was significantly higher than in the normal renal tissue (P <0.05). The RT-PCR data of MMP-2, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 did not show any significant correlation with tumor type or pathologic grade of renal cell carcinoma. MMP-2, MMP-9 and MT1-MMP mRNA expression increased significantly with the TNM stage of the tumor.
Mean MMP-2, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 mRNA expression in the renal cell carcinomas was significantly higher than in the normal renal tissue.
PMCID: PMC3548713  PMID: 23281640
Matrix metalloproteinase; Tissue inhibitor of metalloproteinase; Semi-quantitative RT-PCR; Renal cell carcinoma
14.  Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema 
PLoS ONE  2013;8(2):e56352.
Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema.
Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period.
Main Results
Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline.
MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease.
PMCID: PMC3575373  PMID: 23441181
15.  Comparisons of the Various Partial-Thickness Rotator Cuff Tears on MR Arthrography and Arthroscopic Correlation 
Korean Journal of Radiology  2010;11(5):528-535.
To assess the diagnostic performance of MR arthrography in the diagnosis of the various types of partial-thickness rotator cuff tears by comparing the MR imaging findings with the arthroscopic findings.
Materials and Methods
The series of MR arthrography studies included 202 patients consisting of 100 patients with partial-thickness rotator cuff tears proved by arthroscopy and a control group of 102 patients with arthroscopically intact rotator cuffs, which were reviewed in random order. At arthroscopy, 54 articular-sided, 26 bursal-sided, 20 both articular- and bursal-sided partial-thickness tears were diagnosed. The MR arthrographies were analyzed by two radiologists for articular-sided tears, bursal-sided tears, and both articular- and bursal-sided tears of the rotator cuff. The sensitivity and specificity of each type of partial-thickness tears were determined. Kappa statistics was calculated to determine the inter- and intra-observer agreement of the diagnosis of partial-thickness rotator cuff tears.
The sensitivity and specificity of the various types of rotator cuff tears were 85% and 90%, respectively for articular-sided tears, 62% and 95% for bursal-sided tears, as well as 45% and 99% for both articular- and bursal-sided tears. False-negative assessments were primarily observed in the diagnosis of bursal-sided tears. Conversely, both articular- and bursal-sided tears were overestimated as full-thickness tears. Inter-observer agreement was excellent for the diagnosis of articular-sided tears (k = 0.70), moderate (k = 0.59) for bursal-sided tears, and fair (k = 0.34) for both articular- and bursal-sided tears, respectively. Intra-observer agreement for the interpretation of articular- and bursal-sided tears was excellent and good, respectively, whereas intra-observer agreement for both articular- and bursal-sided tears was moderate.
MR arthrography is a useful diagnostic tool for partial-thickness rotator cuff tears, but has limitations in that it has low sensitivity in bursal- and both articular- and bursal-sided tears. In addition, it shows only fair inter-observer agreement when it comes to predicting both articular- and bursal-sided tears.
PMCID: PMC2930161  PMID: 20808696
Shoulder; MR arthrography; Rotator cuff; Partial-thickness tear
16.  Classification and Clinical Significance of Acromial Spur in Rotator Cuff Tear: Heel-type Spur and Rotator Cuff Tear 
Acromial spurs reportedly relate to the impingement syndrome and rotator cuff tears. We classified the morphologic characteristics of the acromion (shape and thickness) and acromial spurs and determined whether they correlated with rotator cuff tears. We measured acromial shape and thickness using simple radiography and MR arthrography or CT arthrography in 106 patients with full-thickness rotator cuff tears and in 102 patients without tears. Acromial spurs could be classified morphologically into six types: heel, lateral/anterior traction, lateral/anterior bird beak, and medial. We found acromial spurs in 142 of the 208 patients (68%), and their incidence increased with age. The acromial spur was more common in the cuff tear group. The heel type was most common and detected in 59 patients (56%) in the cuff tear group and in 36 patients (35%) in the control group. The flat acromion was more common (60%) than curved and hooked acromion; however, there was no major difference between acromial shape and cuff tear. The mean acromial thickness was 8.0 mm, and the cuff tear group had thicker acromion. These data suggest acromial spurs can be classified according to the distinct morphology, and the most common heel-type spur might be a risk factor for full-thickness rotator cuff tears.
Level of Evidence: Level IV, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2865608  PMID: 19760471
17.  Membrane Type-1 Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases-2 RNA Levels Mimic Each Other during Xenopus laevis Metamorphosis 
PLoS ONE  2007;2(10):e1000.
Matrix metalloproteinases (MMPs) and their endogenous inhibitors TIMPs (tissue inhibitors of MMPs), are two protein families that work together to remodel the extracellular matrix (ECM). TIMPs serve not only to inhibit MMP activity, but also aid in the activation of MMPs that are secreted as inactive zymogens. Xenopus laevis metamorphosis is an ideal model for studying MMP and TIMP expression levels because all tissues are remodeled under the control of one molecule, thyroid hormone. Here, using RT-PCR analysis, we examine the metamorphic RNA levels of two membrane-type MMPs (MT1-MMP, MT3-MMP), two TIMPs (TIMP-2, TIMP-3) and a potent gelatinase (Gel-A) that can be activated by the combinatory activity of a MT-MMP and a TIMP. In the metamorphic tail and intestine the RNA levels of TIMP-2 and MT1-MMP mirror each other, and closely resemble that of Gel-A as all three are elevated during periods of cell death and proliferation. Conversely, MT3-MMP and TIMP-3 do not have similar RNA level patterns nor do they mimic the RNA levels of the other genes examined. Intriguingly, TIMP-3, which has been shown to have anti-apoptotic activity, is found at low levels in tissues during periods of apoptosis.
PMCID: PMC1991586  PMID: 17912339
18.  Combined determination of plasma MMP2, MMP9, and TIMP1 improves the non-invasive detection of transitional cell carcinoma of the bladder 
BMC Urology  2006;6:19.
Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play a major role in the maintenance of extracellular matrix homeostasis and are involved in the process of tumour invasion and metastasis in several malignant tumour entities. The goal of this study is to evaluate the diagnostic value of various circulating MMPs and TIMPs in blood plasma for a non-invasive detection of transitional cell carcinoma of the bladder (TCC).
In this study the concentrations of MMP1, MMP2, MMP3, MMP9, their inhibitors TIMP1, TIMP2, and the MMP1/TIMP1-complex (MTC1) were quantified in blood plasma with the sandwich enzyme-linked immunosorbent assay (ELISA). Blood plasma samples were investigated from 68 patients (non-metastasized, n = 57 and metastasized, n = 11) with TCC of the bladder and from 79 healthy controls. The mROC program was used to calculate the best two- and three- marker combinations. The diagnostic values for all single markers and the marker combinations were estimated both by the overall diagnostic performance index area under the ROC curve (AUC) and the sensitivity and specificity at cutoff limits with the highest diagnostic accuracy and at the 90% and 95% limits of sensitivity and specificity, respectively.
The median MMP2 concentration was elevated in blood plasma in all patient groups with TCC in comparison to the controls (p < 0.001). The concentrations of TIMP1, TIMP2, and MTC1 in plasma probes were significantly lower from patients with non-metastasized TCC compared to the controls. MMP2 tested alone reached the highest sensitivity and specificity at 75%, respectively. The sensitivity and specificity increased when tested in combination with MMP9 and TIMP1 (97%, 94%, respectively). The combination of MMP9 and TIMP1 also showed an improved sensitivity (80%) and specificity (99%) than tested alone.
MMP2 is a statistically significant marker in blood plasma for bladder cancer detection with an increased diagnostic value in combination with MMP9 and TIMP1. This study showed that the highest sensitivities and specificities are not obtained by testing each marker alone. As shown by the best two-marker combination, which includes MMP9 and TIMP1, the optimized combination does not always include the best single markers.
PMCID: PMC1560390  PMID: 16901349
19.  Imbalances between Matrix Metalloproteinases (MMPs) and Tissue Inhibitor of Metalloproteinases (TIMPs) in Maternal Serum during Preterm Labor 
PLoS ONE  2012;7(11):e49042.
Matrix metalloproteinases (MMPs) are involved in remodeling of the extracellular matrix (ECM) during pregnancy and parturition. Aberrant ECM degradation by MMPs or an imbalance between MMPs and their tissue inhibitors (TIMPs) have been implicated in the pathogenesis of preterm labor, however few studies have investigated MMPs or TIMPs in maternal serum. Therefore, the purpose of this study was to determine serum concentrations of MMP-3, MMP-9 and all four TIMPs as well as MMP:TIMP ratios during term and preterm labor.
A case control study with 166 singleton pregnancies, divided into four groups: (1) women with preterm birth, delivering before 34 weeks (PTB); (2) gestational age (GA) matched controls, not in preterm labor; (3) women at term in labor and (4) at term not in labor. MMP and TIMP concentrations were measured using Luminex technology.
MMP-9 and TIMP-4 concentrations were higher in women with PTB vs. GA matched controls (resp. p = 0.01 and p<0.001). An increase in MMP-9:TIMP-1 and MMP-9:TIMP-2 ratio was observed in women with PTB compared to GA matched controls (resp. p = 0.02 and p<0.001) as well as compared to women at term in labor (resp. p = 0.006 and p<0.001). Multiple regression results with groups recoded as three key covariates showed significantly higher MMP-9 concentrations, higher MMP-9:TIMP-1 and MMP-9:TIMP-2 ratios and lower TIMP-1 and -2 concentrations for preterm labor. Significantly higher MMP-9 and TIMP-4 concentrations and MMP-9:TIMP-2 ratios were observed for labor.
Serum MMP-9:TIMP-1 and MMP-9:TIMP-2 balances are tilting in favor of gelatinolysis during preterm labor. TIMP-1 and -2 concentrations were lower in preterm gestation, irrespective of labor, while TIMP-4 concentrations were raised in labor. These observations suggest that aberrant serum expression of MMP:TIMP ratios and TIMPs reflect pregnancy and labor status, providing a far less invasive method to determine enzymes essential in ECM remodeling during pregnancy and parturition.
PMCID: PMC3493509  PMID: 23145060
20.  Predictors of Pain and Function in Patients With Symptomatic, Atraumatic Full-Thickness Rotator Cuff Tears 
Although the prevalence of full-thickness rotator cuff tears increases with age, many patients are asymptomatic and may not require surgical repair. The factors associated with pain and loss of function in patients with rotator cuff tears are not well defined.
To determine which factors correlate with pain and loss of function in patients with symptomatic, atraumatic full-thickness rotator cuff tears who are enrolled in a structured physical therapy program.
Study Design
Cross-sectional study; Level of evidence, 3.
A multicenter group enrolled patients with symptomatic, atraumatic rotator cuff tears in a prospective, nonrandomized cohort study evaluating the effects of a structured physical therapy program. Time-zero patient data were reviewed to test which factors correlated with Western Ontario Rotator Cuff (WORC) index and American Shoulder and Elbow Surgeons (ASES) scores.
A total of 389 patients were enrolled. Mean ASES score was 53.9; mean WORC score was 46.9. The following variables were associated with higher WORC and ASES scores: female sex (P = .001), education level (higher education, higher score; P <.001), active abduction (degrees; P = .021), and strength in forward elevation (P = .002) and abduction (P = .007). The following variables were associated with lower WORC and ASES scores: male sex (P = .001), atrophy of the supraspinatus (P = .04) and infraspinatus (P = .003), and presence of scapulothoracic dyskinesia (P < .001). Tear size was not a significant predictor (WORC) unless comparing isolated supraspinatus tears to supraspinatus, infraspinatus, and subscapularis tears (P = .004). Age, tear retraction, duration of symptoms, and humeral head migration were not statistically significant.
Nonsurgically modifiable factors, such as scapulothoracic dyskinesia, active abduction, and strength in forward elevation and abduction, were identified that could be addressed nonoperatively with therapy. Therefore, physical therapy for patients with symptomatic rotator cuff tears should target these modifiable factors associated with pain and loss of function.
PMCID: PMC3632074  PMID: 22095706
rotator cuff tear; nonoperative treatment; WORC score; ASES score
21.  Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis 
Annals of the Rheumatic Diseases  2000;59(6):455-461.
OBJECTIVE—Matrix metalloproteinases (MMPs) are expressed in joint tissues of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). The objective of this study was to define the steady state levels of seven different MMPs and two tissue inhibitors of metalloproteinases (TIMPs) as well as the potential metalloproteinase activity in the synovial fluid (SF) to provide more insight into the role of MMPs in cartilage destruction in RA and OA.
METHODS—Levels of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, TIMP-1, and TIMP-2 in SF aspirated from knee joints of 97 patients with RA and 103 patients with OA were measured by the corresponding one step sandwich enzyme immunoassays. Proteolytic activity of MMPs in these SFs was examined in an assay using [3H]carboxymethylated transferrin substrate in the presence of inhibitors of serine and cysteine proteinases after activation with p-aminophenylmercuric acetate (APMA). Destruction of RA knee joints was radiographically evaluated.
RESULTS—Levels of MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9 were significantly higher in RA SF than in OA SF. MMP-7 and MMP-13 were detectable in more than 45% of RA SFs and in less than 20% of OA SFs, respectively. Among the MMPs examined, MMP-3 levels were extremely high compared with those of other MMPs. Direct correlations were seen between the levels of MMP-1 and MMP-3 and between those of MMP-8 and MMP-9 in RA SF. Although the levels of MMP-1 and MMP-3 increased even in the early stage of RA, those of MMP-8 and MMP-9 were low in the early stage and increased with the progression of RA. Molar ratios of the total amounts of the MMPs to those of the TIMPs were 5.2-fold higher in patients with RA than in OA, which was significant. APMA-activated metalloproteinase activity in SF showed a similar result, and a direct correlation was seen between the molar ratios and the activity in RA SF.
CONCLUSIONS—Our results show that high levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and TIMP-1 are present in RA SF and suggest that once these MMPs are fully activated, they have an imbalance against TIMPs, which may contribute to the cartilage destruction in RA.

PMCID: PMC1753174  PMID: 10834863
22.  Healed Cuff Repairs Impart Normal Shoulder Scores in Those 65 Years of Age and Older 
It is unclear whether repaired rotator cuffs heal in older patients and whether the function in those shoulders compares with those of similarly aged patients with untreated tears.
We questioned whether, in patients 65 years of age and older, shoulders with rotator cuff repairs that remained intact would have Simple Shoulder Test (SST) scores and Constant scores similar to those of untreated individuals with intact rotator cuffs.
We retrospectively reviewed 39 patients (42 shoulders) 65 years of age and older in whom 42 full-thickness rotator cuff tears were repaired with a mini open technique. All patients completed SST and Constant scores 12 to 60 months postoperatively; all patients also had ultrasound at those times to assess the status of the repair. These findings were compared with 200 untreated similarly aged shoulders assessed in the same fashion.
Shoulders with healed repairs (33 of 42) had similar mean SST scores and Constant scores to those in untreated shoulders with intact rotator cuffs. Those with healed repairs also had higher SST and Constant scores than those with unhealed repairs. Finally, shoulders with healed repairs had higher SST and Constant scores than those with untreated tears.
When rotator cuffs healed the function was comparable to that of similarly-aged patients without tears and better than that of patients with untreated tears.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2865609  PMID: 19763715
23.  Levels of Circulating TIMP-2 and MMP2-TIMP2 Complex Are Decreased in Squamous Cervical Carcinoma 
Background. The role of matrix metalloproteinase-2 and -9 (MMP-2, MMP-9) in matrix degradation and metastasis has been described in various tumors. Their action is inhibited by their natural tissue inhibitor molecules TIMP-1 and -2. Methods. The study population consisted of 12 squamous cervical carcinoma patients and 27 healthy volunteer control patients. MMP-9, MMP-2-TIMP-2 complex, TIMP-1, and TIMP-2 were analyzed from serum samples using enzyme-linked immunoassay (ELISA). Results. The mean levels of serum TIMP-2 and of MMP-2-TIMP-2 complex were higher in healthy controls compared to patients with a malignant tumor. Serum TIMP-2 values decreased significantly from healthy controls (median 323 μg/l, range 305–342 μg/l) to malignant (median 136 μg/l, range 120–151 μg/l) squamous cervical carcinoma patients (P < .000). Also, serum proMMP2-TIMP2 complex values decreased from control patients to squamous cervical carcinoma patients (P < .006). Conclusion. This paper shows that the levels of circulating TIMP-2 and that of MMP-2-TIMP-2 complex are lower in squamous cervical carcinoma patients than in healthy women.
PMCID: PMC2910473  PMID: 20671952
24.  Indications for Surgery in Clinical Outcome Studies of Rotator Cuff Repair 
Full-thickness tears of the rotator cuff are common, but there is no clear consensus regarding indications for rotator cuff surgery. Because some patients with full-thickness rotator cuff tears who are asymptomatic or symptomatic can be successfully treated nonoperatively, clinical outcome studies of rotator cuff repair should describe the subjects in detail to allow appropriate interpretation of the results. However, we hypothesized the indications for surgery are poorly described in outcome studies of rotator cuff surgery. We undertook a detailed literature review over 11 years of six major orthopaedic journals to assess whether the indications for surgery were described adequately in studies of rotator cuff repair. Eighty-six papers fit the criteria for the study and were reviewed. Limitations of activities of daily living (31%), failure of nonoperative treatment (52%), duration of nonoperative treatment (26%), and history of nocturnal pain (16%) were reported in a minority of papers overall. The patients’ characteristics and indications for surgery were not described in a majority of clinical outcome studies of rotator cuff repair. It is important for these factors to be considered and reported because, without this information, the reasons for and results of rotator cuff repair are difficult to interpret.
Level of Evidence: Level III, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2628527  PMID: 18949526
25.  Activities of matrix metalloproteinases and tissue inhibitor of metalloproteinase-2 in idiopathic hemotympanum and otitis media with effusion 
Acta oto-laryngologica  2008;128(2):144-150.
The expression profile of matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinase-2 (TIMP-2) was specific to the type of middle ear effusion. Further studies are necessary for elucidating its correlation with the sequelae of otitis media with effusion (OME) and idiopathic hemotympanum.
We aimed to investigate the relative activities of gelatinases (MMP-2 and 9), stromelysin-1 (MMP-3), matrilysin-1 (MMP-7) as well as measuring TIMP-2 levels in the serous and mucous effusions of OME and hemorrhagic effusion of the idiopathic hemotympanum.
Middle ear effusions were collected from patients with OME and idiopathic hemotympanum, and were classified as mucoid, serous or hemorrhagic. MMP activity in the effusion samples was examined by gelatin and casein zymography. Levels of TIMP-2 were measured by ELISA. Human temporal bones sections, with and without otitis media (OM), were examined histologically.
One case showed tympanic membrane thinning in the OM group, but none in the control group. While MMP-2 was present in all effusions, the active form of MMP-2 was found only in mucous effusions. MMP-3 and MMP-7 activity was detected only in the mucous effusions. MMP-9 exhibited activity in all effusions, with the highest levels in mucous effusions. TIMP-2 levels were markedly elevated in serous effusions.
PMCID: PMC2577605  PMID: 17851959
Matrix metalloproteinase; Tissue inhibitor of metalloproteinase; Otitis media with effusion; Idiopathic hemotympanum

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